Published Ahead of Print on December 2, 2013 as 10.1200/JCO.2013.50.5305 The latest version is at http://jco.ascopubs.org/cgi/doi/10.1200/JCO.2013.50.5305

JOURNAL OF CLINICAL ONCOLOGY

O R I G I N A L

R E P O R T

Randomized Phase III Trial of Temsirolimus and Bevacizumab Versus Interferon Alfa and Bevacizumab in Metastatic Renal Cell Carcinoma: INTORACT Trial Brian I. Rini, Joaquim Bellmunt, Jill Clancy, Kongming Wang, Andreas G. Niethammer, Subramanian Hariharan, and Bernard Escudier See accompanying articles doi: 10.1200/JCO.2013.50.3961 Brian I. Rini, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH; Joaquim Bellmunt, University Hospital del Mar-IMIM, Barcelona, Spain; Jill Clancy, Kongming Wang, Andreas G. Niethammer, Subramanian Hariharan, Pfizer, New York, NY; and Bernard Escudier, Institut Gustave Roussy, Villejuif, France. Published online ahead of print at www.jco.org on December 2, 2013. This study was sponsored by Wyeth Research, which was acquired by Pfizer in October 2009. Bevacizumab and interferon alfa (Roferon) were provided by Genentech/Roche. Presented in part at the 37th Congress of the European Society for Medical Oncology, September 28-October 2, 2012, Vienna, Austria. Terms in blue are defined in the glossary, found at the end of this article and online at www.jco.org. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article. Clinical trial information: NCT00631371. Corresponding author: Brian I. Rini, MD, Department of Solid Tumor Oncology and Urology, Cleveland Clinic Taussig Cancer Institute, 9500 Euclid Ave, Desk R35, Cleveland, OH 44195; e-mail: [email protected] © 2013 by American Society of Clinical Oncology

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T

Purpose To prospectively determine the efficacy of combination therapy with temsirolimus plus bevacizumab versus interferon alfa (IFN) plus bevacizumab in metastatic renal cell carcinoma (mRCC). Patients and Methods In a randomized, open-label, multicenter, phase III study, patients with previously untreated predominantly clear-cell mRCC were randomly assigned, stratified by prior nephrectomy and Memorial Sloan-Kettering Cancer Center prognostic group, to receive the combination of either temsirolimus (25 mg intravenously, weekly) or IFN (9 MIU subcutaneously thrice weekly) with bevacizumab (10 mg/kg intravenously, every 2 weeks). The primary end point was independently assessed progression-free survival (PFS). Results Median PFS in patients treated with temsirolimus/bevacizumab (n ⫽ 400) versus IFN/ bevacizumab (n ⫽ 391) was 9.1 and 9.3 months, respectively (hazard ratio [HR], 1.1; 95% CI, 0.9 to 1.3; P ⫽ .8). There were no significant differences in overall survival (25.8 ␯ 25.5 months; HR, 1.0; P ⫽ .6) or objective response rate (27.0% ␯ 27.4%) with temsirolimus/bevacizumab versus IFN/bevacizumab, respectively. Patients receiving temsirolimus/bevacizumab reported significantly higher overall mean scores in the Functional Assessment of Cancer Therapy– Kidney Symptom Index (FKSI) –15 and FKSI-Disease Related Symptoms subscale compared with IFN/bevacizumab (indicating improvement); however, no differences in global health outcome measures were observed. Treatment-emergent all-causality grade ⱖ 3 adverse events more common (P ⬍ .001) with temsirolimus/bevacizumab were mucosal inflammation, stomatitis, hypophosphatemia, hyperglycemia, and hypercholesterolemia, whereas neutropenia was more common with IFN/bevacizumab. Incidence of pneumonitis with temsirolimus/bevacizumab was 4.8%, mostly grade 1 or 2. Conclusion Temsirolimus/bevacizumab combination therapy was not superior to IFN/bevacizumab for first-line treatment in clear-cell mRCC. J Clin Oncol 31. © 2013 by American Society of Clinical Oncology

0732-183X/13/3199-1/$20.00 DOI: 10.1200/JCO.2013.50.5305

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INTRODUCTION

The treatment of advanced renal cell carcinoma (RCC) has been transformed over recent years with introduction of molecularly targeted therapies against vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR).1-8 Temsirolimus is a highly specific inhibitor of mTOR, the signaling pathway of which is altered in RCC with clear cell histology, of advanced

stage, or with poor prognostic features.9-11 Temsirolimus is an approved treatment for patients with advanced RCC, having demonstrated antitumor activity in a phase II study of predominantly cytokine-pretreated patients with advanced RCC12 and, in the pivotal phase III trial, improved overall survival (OS) and progression-free survival (PFS) compared with interferon alfa (IFN) as first-line treatment in patients with multiple poor prognostic factors.2 © 2013 by American Society of Clinical Oncology

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Rini et al

Bevacizumab is an antiangiogenic monoclonal antibody against VEGF with activity in RCC.4,8,13,14 The majority of RCC tumors, most notably in clear-cell RCC arising from inactivation of the von HippelLindau (VHL) tumor suppressor gene, are highly vascular and associated with overexpression of VEGF.13-15 In two large phase III trials, the addition of bevacizumab to IFN for first-line treatment of clear-cell metastatic RCC (mRCC) showed superior efficacy (PFS) compared with IFN alone.4,8 On the basis of these results, the regimen of IFN in combination with bevacizumab is presently the only combination therapy approved for treatment of RCC. Both temsirolimus and bevacizumab have single-agent activity in RCC, but the objective response rate (ORR) of each agent alone is modest.2,16,17 Because these agents target two different mechanisms of RCC pathogenesis, the combination of temsirolimus and bevacizumab has the potential to further improve efficacy and possibly overcome or delay resistance to bevacizumab by concomitantly blocking alternative signaling pathways. In a preclinical study, the combination of temsirolimus and bevacizumab was found to induce tumor regression in nude mice bearing A498 renal tumors on their flanks, whereas neither drug was able to induce tumor regression as monotherapy, suggesting a potentially additive or synergistic effect of the combination treatment (data on file, Wyeth, Collegeville, PA). Safety data obtained from earlier clinical trials of single-agent treatment suggested that temsirolimus and bevacizumab displayed nonoverlapping toxicity profiles.15,16,18,19 A phase I portion (n ⫽ 12) of a phase I/II study in previously treated patients with RCC demonstrated an acceptable safety profile for temsirolimus in combination with bevacizumab at full doses of each agent, with promising activity (seven partial responses).20 Investigation of Torisel and Avastin Combination Therapy trial (INTORACT), an international, randomized, open-label phase III trial, was undertaken to directly compare combination treatment with temsirolimus/bevacizumab against standard combination therapy of IFN/bevacizumab for first-line treatment of patients with advanced RCC.

PATIENTS AND METHODS Patients Key eligibility criteria were histologically or cytologically confirmed advanced (stage IV or recurrent) RCC with a majority component of clear cell histology, no prior systemic treatment for RCC, age ⱖ 18 years, Karnofsky performance status ⱖ 70%, life expectancy ⱖ 12 weeks, at least one measurable lesion per Response Evaluation Criteria for Solid Tumors (RECIST) version 1.0,21 and adequate organ function. Patients were excluded if they had CNS metastasis, history of major thrombotic or bleeding episode within 6 months, inadequately controlled hypertension (systolic blood pressure ⱖ 150 mmHg and/or diastolic blood pressure ⱖ 100 mmHg on medication), major surgery or radiation therapy within 4 weeks, or chronic use of antiplatelet agents or corticosteroids. All patients provided written informed consent. Study Design and Treatments This randomized, multicenter, phase III trial was conducted at 124 sites in 29 countries. After screening and enrollment, patients were randomly assigned (one to one) to receive either intravenous (IV) temsirolimus (25 mg weekly) plus bevacizumab (10 mg/kg IV every 2 weeks) or IFN (9 million U [MIU] subcutaneously thrice weekly) plus bevacizumab (10 mg/kg IV every 2 weeks). Patients were stratified according to baseline Memorial SloanKettering Cancer Center (MSKCC) prognostic group (favorable, intermediate, or poor)22 and prior nephrectomy (yes or no). A computerized centrally located randomization system was used to assign patient identification and treatment. Patients received treatment until disease progression, unacceptable toxicity, withdrawal of consent, or death. Toxicity-related dose reductions were allowed for temsirolimus and IFN, but not for bevacizumab. After treatment discontinuation, patients were observed for survival, initiation of subsequent anticancer therapy, and treatment-related serious adverse events (AEs). The primary end point was independently assessed PFS, defined as time from randomization to either disease progression per RECIST or death by any cause, whichever came first. Secondary end points were investigator-assessed PFS, independently assessed ORR, OS, and safety. Disease-related symptoms and quality of life were assessed as exploratory objectives. The study was approved by the institutional review board or independent ethics committee of each center and was conducted in accordance with

Randomly assigned (N = 791)

Assigned to TEM/BEV (n = 400)

Assigned to IFN/BEV (n = 391)

Did not receive treatment (n = 7)

Received treatment

(n = 393)*

Discontinued treatments (n = 372) Disease progressed (n = 217) Had adverse events (n = 80) Patient requested (n = 36) Symptoms deteriorated (n = 12) (n = 8) Had noncompliance Had protocol violation (n = 7) Died (n = 4) Investigator requested (n = 4) (n = 4) Had other reasons Continue on treatment (n = 21) In follow-up (n = 123)

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© 2013 by American Society of Clinical Oncology

Received treatment

(n = 391)

Discontinued treatments (n = 354) Disease progressed (n = 217) Had adverse events (n = 67) (n = 44) Patient requested Symptoms deteriorated (n = 11) Had noncompliance (n = 2) Had protocol violation (n = 4) (n = 1) Died (n = 6) Investigator requested Had other reasons (n = 2)

Fig 1. CONSORT diagram of patient disposition. (*) One patient received only one of the allocated treatment drugs (bevacizumab). BEV, bevacizumab; IFN, interferon alfa; TEM, temsirolimus.

Continue on treatment (n = 37) In follow-up (n = 107)

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Temsirolimus/Bevacizumab v Interferon Alfa/Bevacizumab in mRCC

Study Assessments Radiographic evaluations were conducted at screening and every 8 weeks, and tumor progression was assessed both by investigators and by an independent blinded assessment (BioClinica, [formerly Bio-Imaging Technologies], Newtown, PA). Images were read and reviewed by two independent radiologists and, if disagreed, adjudicated by a third reviewer. The reviewers were only given the information on the patient’s radiation and surgery history. Bone scan was required at screening and during treatment if signs or symptoms of bone metastases developed. For the primary efficacy end point (PFS), results underwent independent radiographic assessment in accordance with RECIST. Safety and tolerability were assessed throughout the study by physical/clinical examination, hematology and biochemistry tests, and monitoring AEs, which were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 3.0. Health outcomes were assessed at screening, every 8 weeks, and at the end of treatment to explore the patient’s own perceptions about his or her quality of life. Assessments were conducted using the Functional Assessment of Cancer Therapy–Kidney Symptom Index (FKSI) –15, which contains 15 questions representing concerns specific to patients with advanced kidney cancer; FKSI-Disease Related Symptoms (FKSI-DRS) subscale; European Quality of Life-5 Dimensions (EQ-5D), which evaluates five domains (Mobility, Self-Care, Usual Activity, Pain/Discomfort, and Anxiety/Depression); and EQ-5D visual analog scale (EQ-VAS). Statistical Considerations The study was originally designed to detect a hazard ratio (HR) of 0.77 (30% improvement in median PFS: 10.2 months for IFN/bevacizumab4 and

13.3 months for temsirolimus/bevacizumab) with 80% power using a onesided stratified log-rank test at the 2.5% significance level, with one primary analysis and no interim analysis. A sample size of 800 patients was required for randomization to observe 446 events (death or progression per independent assessment) for the primary analysis, assuming a 15% dropout rate from lost to follow-up and other reasons. Subsequently, one interim analysis based on investigator-assessed PFS was added, before any knowledge of efficacy results, at approximately 236 observed events, and the number of independently assessed events in the final analysis was revised upward to 472. A nonbinding futility boundary, specified by the Pampallona-Tsiatis power spending function (parameter value, 0), and an efficacy boundary, specified by ␥ (⫺20) ␣-spending function, was calculated based on a number of observed PFS events at interim analysis. Because the trial was not to be stopped for efficacy (but for futility only) at interim analysis, testing at the final analysis was done at the nominal 0.025 significance level (one-sided). With 236 observed PFS events, the futility boundary would be crossed if the observed HR was greater than 0.9262. PFS in the temsirolimus/bevacizumab arm was compared with the IFN/ bevacizumab arm using a stratified log-rank test at a 2.5% (one-sided) significance level; HRs and corresponding 95% CIs were generated based on the stratified Cox proportional hazards regression model. The median time to event was estimated using the Kaplan-Meier method. Comparative analysis between the two treatment arms for OS was determined by stratified log-rank

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Table 1. Demographic and Baseline Characteristics (intent-to-treat population)

Age, years Median Range Sex Male Female Race White Asian Other Karnofsky performance status ⱖ 90% 80% 70% Unknown Prior nephrectomyⴱ Prior radiotherapy MSKCC prognostic group (no. of risk factors†) Favorable (0) Intermediate (1-2) Poor (ⱖ 3)

Interferon Alfa/ Bevacizumab (n ⫽ 391)

No.

No.

%

59 22-87

%

58 23-81

286 114

72 29

270 121

69 31

327 47 26

82 12 7

332 50 9

85 13 2

279 100 20 1 338 44

70 25 5 ⬍1 85 11

288 72 30 1 335 36

74 18 8 ⬍1 86 9

0.8

0.6

0.4

0.2 HR, 1.1; 95% CI, 0.9 to 1.3; P = .8

8

12

256 230

161 167

95 114

16

20

24

28

32

36

40

4 12

2 6

1 2

Time (months)

No. at risk TEM+BEV IFN+BEV

B

4

400 391

59 78

36 60

26 32

14 22

1.0

TEM+BEV IFN+BEV

0.8

123 230 47

31 58 12

114 237 40

0.6

0.4

0.2 HR, 1.0; 95% CI, 0.9 to 1.3; P = .6

29 61 10

Abbreviation: MSKCC, Memorial Sloan-Kettering Cancer Center. ⴱ Per clinical database. †Includes serum hemoglobin below normal, serum lactate dehydrogenase ⬎ 1.5⫻ upper limit of normal, corrected serum calcium ⬎ 10 mg/dL, Karnofsky performance status ⬍ 80%, and time from diagnosis to randomization ⬍ 1 year.22

www.jco.org

TEM+BEV IFN+BEV

0

Overall Survival (probability)

Characteristic

Temsirolimus/ Bevacizumab (n ⫽ 400)

1.0

Progression-Free Survival (probability)

the Declaration of Helsinki, the International Conference on Harmonization/ Good Clinical Practice, and local regulatory requirements.

0 No. at risk TEM+BEV IFN+BEV

4

8

12 16 20 24 28 32 36 40 44 48

351 346

310 308

262 271

Time (months) 400 391

231 195 243 201

156 122 146 114

74 72

38 34

13 9

3 0

Fig 2. Kaplan-Meier curves of (A) progression-free survival assessed by independent assessment and (B) overall survival assessed by investigators. BEV, bevacizumab; HR, hazard ratio; IFN, interferon alfa; TEM, temsirolimus.

© 2013 by American Society of Clinical Oncology

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Rini et al

test at the 2.5% (one-sided) significance level. ORRs were compared using the Cochran-Mantel-Haenszel test stratified by prior nephrectomy and baseline MSKCC risk factors, and health outcomes with a repeated-measures mixedeffects model with time as continuous variable and baseline scores as covariate. The minimally important difference was predefined as 3 to 5 points for the FKSI-1523 and 2 to 3 points for FKSI-DRS24 to determine a clinically meaningful difference. East version 5 computer software (Cytel Software Corporation, Cambridge, MA) was used to calculate sample size and stopping boundaries; all other statistical analyses were performed with SAS version 9.1.3 or later (SAS Institute, Cary, NC).

RESULTS

Patients From April 10, 2008, to October 19, 2010, 791 patients were randomly assigned to receive temsirolimus/bevacizumab (n ⫽ 400) or IFN/bevacizumab (n ⫽ 391; Fig 1). Seven patients randomly assigned to the temsirolimus/bevacizumab arm did not receive study treatment, and another patient received bevacizumab monotherapy. Baseline demographics and clinical characteristics were well balanced between the two treatment arms (Table 1). Overall, most patients were male (70%), white (83%), younger than 65 years (73%), and had a Karnofsky performance status ⱖ 80% (93%), favorable or intermediate MSKCC prognostic group (89%), and prior nephrectomy (85%). As of the data cutoff date (April 19, 2012), 372 (95%) and 354 (91%) patients in the temsirolimus/bevacizumab and IFN/bevaci-

zumab arm, respectively, discontinued treatment. The main reasons for treatment discontinuation were disease progression (58% ␯ 61%, respectively) and AEs (22% ␯ 19%, respectively; Fig 1). At the time of data cutoff, in the temsirolimus/bevacizumab and IFN/bevacizumab arm, respectively, 21 and 37 patients remained on treatment, an additional 123 and 107 patients were still alive on study in long-term follow-up, and 210 and 199 patients had died. Efficacy The interim futility analysis occurred in June 2010 after 50% of PFS events and the external data monitoring committee recommended the study to continue as planned. For the final analysis, a total of 489 patients (62%) had primary outcome events (427 independently assessed progressions and 62 deaths). On the basis of the final analysis, there was no significant improvement in the primary end point of independently assessed PFS in patients assigned to temsirolimus/bevacizumab compared with IFN/bevacizumab (Fig 2A). Median PFS was 9.1 months (95% CI, 8.1 to 10.2 months) for temsirolimus/bevacizumab and 9.3 months (95% CI, 9.0 to 11.2 months) for IFN/bevacizumab, with an estimated HR of 1.1 (95% CI, 0.9 to 1.3; stratified one-sided P ⫽ .8). Similar results were obtained for PFS by investigator assessment: median PFS 9.1 months (95% CI, 8.1 to 10.5 months) with temsirolimus/bevacizumab and 10.8 months (95% CI, 9.1 to 11.2 months) with IFN/ bevacizumab (HR, 1.1; 95% CI, 1.0 to 1.4; stratified one-sided P ⫽ .9). PFS results from prespecified subset analyses, including by

Table 2. Independently Assessed Progression-Free Survival by Stratification Factors and Demographic Characteristics (intent-to-treat population) Temsirolimus/Bevacizumab (n ⫽ 400) Factor Stratification factors at randomization Prior nephrectomy No Yes MSKCC prognostic group (no. of risk factors) Favorable (0) Intermediate (1-2) Poor (ⱖ 3) Demographic characteristics Age, years ⬍ 65 ⱖ 65 Sex Male Female Race White Asian Region EMA region Non-EMA region United States

Interferon Alfa/Bevacizumab (n ⫽ 391)

95% CI

No.

%

Median PFSⴱ (months)

95% CI

HR†

95% CI

P‡

9.2 9.1

7.2 to 11.1 8.1 to 10.4

57 334

15 85

6.8 10.9

2.4 to 7.5 9.1 to 12.7

0.8 1.1

0.5 to 1.3 0.9 to 1.4

.32 .19

31 58 12

11.0 9.2 4.0

9.0 to 14.5 8.1 to 10.9 3.4 to 7.2

114 237 40

29 61 10

11.2 9.1 2.1

10.7 to 14.9 7.3 to 12.7 1.8 to 5.4

1.2 1.1 0.8

0.8 to 1.6 0.9 to 1.4 0.5 to 1.4

.41 .42 .49

294 106

74 27

9.2 8.5

8.1 to 10.5 7.2 to 12.8

282 109

72 28

9.1 11.6

7.4 to 10.9 7.5 to 16.4

1.0 1.3

0.9 to 1.3 0.9 to 1.8

.72 .23

286 114

72 29

9.1 9.2

7.6 to 10.2 7.2 to 12.7

270 121

69 31

10.0 9.1

9.0 to 12.7 6.9 to 12.6

1.2 0.9

0.9 to 1.4 0.7 to 1.3

.16 .70

327 47

82 12

9.0 9.2

7.4 to 10.2 4.6 to 11.1

332 50

85 13

9.3 7.1

9.0 to 11.6 3.6 to 12.9

1.1 1.1

0.9 to 1.3 0.7 to 1.7

.49 .77

172 216 12

43 54 3

9.1 9.2 5.3

7.4 to 11.1 7.6 to 10.5 3.7 to NE

164 210 17

42 54 4

12.7 8.6 7.5

9.3 to 16.5 7.2 to 10.7 1.8 to NE

1.2 1.0 1.5

0.9 to 1.6 0.8 to 1.3 0.5 to 4.5

.23 .92 .51

No.

%

61 339

15 85

123 230 47

Median PFS (months)



Abbreviations: EMA, European Medicines Agency; HR, hazard ratio; MSKCC, Memorial Sloan-Kettering Cancer Center; NE, not estimable; PFS, progression-free survival. ⴱ Median and CI estimates based on quartile estimates produced using the Kaplan-Meier method. †Compared with interferon alfa/bevacizumab based on an unstratified Cox proportional hazards model. ‡Compared with interferon alfa/bevacizumab based on an unstratified log-rank test.

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© 2013 by American Society of Clinical Oncology

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Temsirolimus/Bevacizumab v Interferon Alfa/Bevacizumab in mRCC

Temsirolimus/ Bevacizumab (n ⫽ 400)

Best observed RECIST response Complete response Partial response Stable disease Progressive disease Indeterminate No postbaseline tumor assessment Death before first postbaseline assessment Unknown Overall objective response rate Complete ⫹ partial response 95% CI Pⴱ

No.

%

No.

%

2 106 218 41 5

⬍1 26.5 54.5 10.3 1.3

6 101 184 69 0

1.5 25.8 47.1 17.6

17

4.3

18

4.6

11 0

2.8

12 1

3.1 ⬍1

108 22.7 to 31.6

27.0

0 -2 -3 -4 -5 -6 -7 -8

TEM+BEV IFN+BEV

-9 -10

107 23.0 to 32.1 1.0

27.4

Abbreviation: RECIST, Response Evaluation Criteria in Solid Tumors.21 ⴱ Based on a Cochran-Mantel-Haenszel test stratified by prior nephrectomy and Memorial Sloan-Kettering Cancer Center risk groups as randomized (two-sided).

stratification factors (Table 2), were consistent with those from the primary analysis; no significant clinical benefit was observed for temsirolimus/bevacizumab in any of the evaluated subgroups (prior nephrectomy, MSKCC prognostic group, age, sex, race, or geographic region). The independently assessed ORR was 27.0% and 27.4% for temsirolimus/bevacizumab and IFN/bevacizumab, respectively (Table 3), with a risk ratio 1.0 (95% CI, 0.8 to 1.3; P ⫽ 1.0) adjusted for the baseline stratification factors. Median duration of objective response was 11.3 months (95% CI, 9.0 to 14.8 months) for temsirolimus/ bevacizumab and 16.6 months (95% CI, 10.8 to 20.3 months) for IFN/bevacizumab. At the time of data cutoff, OS was not statistically different between the two treatment arms (HR, 1.0; 95% CI, 0.9 to 1.3; stratified one-sided P ⫽ 0.6; Fig 2B). Median OS was 25.8 months (95% CI, 21.1 to 30.7 months) in the temsirolimus/bevacizumab arm and 25.5 months (95% CI, 22.4 to 30.8 months) in the IFN/bevacizumab arm. Patient-Reported Outcomes The completion rate for each questionnaire was uniformly high in both treatment arms, with rates above 90% among patients on treatment up to the end of treatment visit. Analyses were based on observed data without imputation for missing data. Patients in the two treatment arms had almost identical mean scores at baseline. Mean changes from baseline for both FKSI-15 and FKSI-DRS are shown in Figure 3. For both questionnaires, the temsirolimus/bevacizumab arm seemed to maintain a higher (ie, better quality of life) mean score over subsequent cycles. A longitudinal mixed-effects model comparison of the two treatment arms showed that the temsirolimus/bevacizumab arm exhibited significantly higher overall mean scores compared with the IFN/bevacizumab arm for both FKSI-15 (estimated means, 43.3 and 41.5, respectively; P ⫽ .002) and FKSI-DRS (estimated means, www.jco.org

1.0 -1

SCR

B

9

25

41

57

73

89 105 121 137 153 169

176 125 170 139

71 100

53 73

35 59

73

89 105 121 137 153 169

EOT

Time (weeks)

No. at risk TEM+BEV IFN+BEV

325 266 318 243

24 34

14 23

6 12

1 7

1 2

208 194

0 -1

FKSI–DRS Change From Baseline

Best Response

Interferon Alfa/Bevacizumab (n ⫽ 391)

A FKSI–15 Change From Baseline

Table 3. Independently Assessed Best Objective Response by RECIST (intent-to-treat population)

-2 -3 -4 -5 -6 TEM+BEV IFN+BEV

-7 -8 SCR

No. at risk TEM+BEV IFN+BEV

9

25

41

57

176 170

126 139

72 100

EOT

Time (weeks) 326 267 317 243

53 73

35 59

24 34

14 23

6 12

1 7

1 2

209 194

Fig 3. Change from baseline in (A) Functional Assessment of Cancer Therapy– Kidney Symptom Index (FKSI) –15 and (B) FKSI-Disease Related Symptoms (DRS) scale. BEV, bevacizumab; EOT, end of treatment; IFN, interferon alfa; SCR, screening; TEM, temsirolimus.

29.2 and 28.0, respectively; P ⬍ .001). However, the differences did not meet the predefined minimally important difference threshold (3 to 5 points for FKSI-15 and 2 to 3 points for FKSI-DRS) and hence were considered not clinically meaningful. On the basis of longitudinal mixed-effects model comparison, no statistically significant differences in EQ-5D and EQ-VAS global health outcome questionnaires were observed between the two treatment arms. Safety and Tolerability A lower percentage of patients received treatment drugs for more than 48 weeks in the temsirolimus/bevacizumab arm compared with patients in the IFN/bevacizumab arm: 27% versus 33% for temsirolimus versus IFN, respectively, and 26% versus 34% for bevacizumab. Dose reduction owing to AEs in the temsirolimus/bevacizumab arm versus the IFN/bevacizumab arm was 30% ␯ 38%, respectively, and treatment delay owing to AEs was 70% ␯ 62%, respectively. The most common AE leading to dose reduction was mucosal inflammation (5.1%) in patients treated with temsirolimus/bevacizumab and asthenia (8.4%) in patients treated with IFN/bevacizumab. Dose delays in both arms were mainly due to proteinuria (17% ␯ 14%, respectively), © 2013 by American Society of Clinical Oncology

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Rini et al

Table 4. Treatment-Emergent Adverse Events of Clinical Interest Reported by ⱖ 15% of Patients in Either Treatment Arm Temsirolimus/ Bevacizumab (n ⫽ 393)

Interferon Alfa/Bevacizumab (n ⫽ 391)

All Grades

Grade ⱖ 3

All Grades

Grade ⱖ 3

Adverse Event

No.

%

No.

%

No.

%

No.

%

Proteinuria Hypertension Diarrhea Hypercholesterolemia Rash Hypertriglyceridemia Mucosal inflammation Decreased appetite Stomatitis Asthenia Fatigue Weight decrease Hyperglycemia Pyrexia Anemia Cough Nausea Peripheral edema Neutropenia Myalgia

141 127 127 125 125 114 106 104 102 96 92 90 86 82 82 77 69 66 18 18

36 32 32 32ⴱ 32ⴱ 29 27ⴱ 26 26ⴱ 24 23 23 22ⴱ 21 21 20 18 17ⴱ 5 5

64 44 17 23 13 27 31 9 27 23 18 7 25 4 36 2 3 4 7 0

16 11 4 6ⴱ 3 7 8ⴱ 2 7ⴱ 6 5 2 6ⴱ 1 9 ⬍1 ⬍1 1 2

106 100 87 38 32 81 39 126 38 111 123 90 18 153 65 70 76 30 65 60

27 26 22 10 8 21 10 32 10 28 31 23 5 39† 17 18 19 8 17† 15†

52 41 8 5 3 16 1 13 6 39 42 14 4 11 32 1 3 3 32 11

13 10 2 1 ⬍1 4 ⬍1 3 2 10 11 4 1 3 8 ⬍1 ⬍1 ⬍1 8† 3†

ⴱ Occurred in a significantly (P ⬍ .001) higher proportion in the temsirolimus/ bevacizumab treatment arm than the interferon alfa/bevacizumab treatment arm. †Occurred in a significantly (P ⬍ .001) higher proportion in the interferon alfa/bevacizumab treatment arm than the temsirolimus/bevacizumab treatment arm.

which was one of the most frequently reported treatment-emergent all-grade AEs (Table 4). Other common AEs were diarrhea, rash, hypercholesterolemia, hypertension, hypertriglyceridemia, mucosal inflammation, decreased appetite, and stomatitis with temsirolimus/ bevacizumab treatment and pyrexia, fatigue, decreased appetite, asthenia, and hypertension with IFN/bevacizumab. Significantly (P ⬍ .001) different AEs between the two treatment arms are indicated in Table 4. In addition, the temsirolimus/bevacizumab arm had a higher frequency of renal AEs, infection, and hypersensitivity, but incidence of respiratory, bleeding, and thrombotic AEs was similar between the two treatment arms. The temsirolimus/bevacizumab arm had a slightly higher incidence of NCI-CTCAE grade ⱖ 3 AEs (80% ␯ 76%, respectively) and serious AEs (45% ␯ 38%, respectively) compared with the IFN/bevacizumab arm. Grade ⱖ 3 mucosal inflammation, stomatitis, hypophosphatemia, hyperglycemia, and hypercholesterolemia occurred at a significantly higher incidence with temsirolimus/ bevacizumab; grade ⱖ 3 neutropenia was statistically higher with IFN/bevacizumab (Table 4). Nineteen patients (4.8%) in the temsirolimus/bevacizumab arm reported pneumonitis, the majority of which was grade 1 or 2. Of the 409 deaths, 61 occurred during treatment or within 30 days of the last dose: 35 patients (9%) in the temsirolimus/bevacizumab arm and 26 patients (7%) in the IFN/bevacizumab arm. The primary cause of death for the majority of patients was disease progression (42% ␯ 44%, temsirolimus/bevacizumab ␯ IFN/bevaci6

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zumab, respectively). Death resulting from treatment-related AEs was slightly less common in patients treated with temsirolimus/bevacizumab (1%) than with IFN/bevacizumab (1.8%). DISCUSSION

In this global randomized phase III study, no differences were observed for PFS, OS, or ORR between the combination regimens of temsirolimus/bevacizumab and IFN/bevacizumab when administered as first-line treatment in patients with advanced RCC. No differential PFS benefit between treatment arms was observed when analyzed in predefined subgroups such as prior nephrectomy, MSKCC risk factors, age, sex, race, or geographic region. Similar ORRs were observed in both treatment arms, although the duration of response was numerically shorter with temsirolimus/bevacizumab than with IFN/bevacizumab. Median OS at the time of data cutoff was more than 2 years in both treatment arms. There was improvement in the FKSI-15 and FKSI-DRS scores with temsirolimus/bevacizumab compared with IFN/bevacizumab, although the differences did not meet the predefined clinically meaningful threshold differences, and no global health outcome differences were observed. AEs observed in this study were consistent with the known safety profiles of temsirolimus, bevacizumab, and IFN. In both treatment arms, frequent grade ⱖ 3 AEs were proteinuria and hypertension, both of which are known adverse effects attributable directly or indirectly to the anti-VEGF effects of bevacizumab.25 In addition, grade ⱖ 3 fatigue and asthenia were more common with IFN/bevacizumab treatment. Incidentally, the common AEs observed with IFN/bevacizumab in this study were comparable to those reported in previous phase III trials evaluating the same combination regimen.4,8 The frequency of some AEs differed between treatment arms in the current study, but were consistent with the unique class-effect toxicities associated with mTOR inhibitors (eg, rash, mucosal inflammation, hypertriglyceridemia, hypercholesterolemia, and hyperglycemia) and IFN (eg, asthenia, fever, anorexia, and chills).2,19,26 The occurrence of grade ⱖ 3 pneumonitis in patients treated with temsirolimus/bevacizumab was 1% in this study, which was similar to that previously reported for temsirolimus alone.18,27 This randomized phase III trial was initiated based on the promising, but preliminary, data observed for temsirolimus/bevacizumab in an open-label, phase I/II study,20,28 which indicated the feasibility of this combination. After the current phase III trial was initiated, results from a randomized phase II trial (TORAVA)29 in previously untreated patients (n ⫽ 171) became available. In TORAVA, the temsirolimus/ bevacizumab combination resulted in higher toxicity than anticipated, which limited the duration of treatment; median PFS of 8.2 months and ORR of 27% with temsirolimus/bevacizumab were lower than with IFN/bevacizumab (16.8 months and 43%, respectively). Of note, results from another randomized phase II trial (BEST),30 evaluating three combinations of targeted therapies (temsirolimus/ bevacizumab, temsirolimus/sorafenib, and bevacizumab/sorafenib), indicated that they do not improve PFS over bevacizumab alone in first-line RCC. Combination treatment with temsirolimus and sunitinib, another antiangiogenic agent, in a phase I trial in advanced RCC was terminated because of dose-limiting toxicity at a low dose for each drug,31 whereas significant toxicities associated with sunitinib in combination with bevacizumab precluded the use of an adequate dosing regimen.32 JOURNAL OF CLINICAL ONCOLOGY

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Temsirolimus/Bevacizumab v Interferon Alfa/Bevacizumab in mRCC

The second approved mTOR inhibitor, everolimus, has also been investigated as combination targeted therapy in advanced RCC. Preliminary reports from an open-label phase II trial of first-line everolimus in combination with bevacizumab have failed to show clinical benefit compared with IFN/bevacizumab (RECORD-2),33 further confirming lack of evidence that combination therapy simultaneously blocking both VEGF and mTOR pathways offers any advantage over IFN/bevacizumab, other approved single agents, or sequential blocking of VEGF and mTOR pathways. In conclusion, temsirolimus/bevacizumab was not superior to IFN/bevacizumab as first-line therapy for patients with clear cell mRCC. Safety data were consistent with known profiles of these agents when given as monotherapy. IFN/bevacizumab remains the only combination regimen with demonstrated benefit for first-line treatment of advanced RCC.

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) and/or an author’s immediate family member(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked

REFERENCES 1. Motzer RJ, Hutson TE, Tomczak P, et al: Sunitinib versus interferon alfa in metastatic renalcell carcinoma. N Engl J Med 356:115-124, 2007 2. Hudes G, Carducci M, Tomczak P, et al: Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 356:2271-2281, 2007 3. Sternberg CN, Davis ID, Mardiak J, et al: Pazopanib in locally advanced or metastatic renal cell carcinoma: Results of a randomized phase III trial. J Clin Oncol 28:1061-1068, 2010 4. Escudier B, Pluzanska A, Koralewski P, et al: Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: A randomised, double-blind phase III trial. Lancet 370:2103-2111, 2007 5. Motzer RJ, Escudier B, Oudard S, et al: Phase 3 trial of everolimus for metastatic renal cell carcinoma: Final results and analysis of prognostic factors. Cancer 116:4256-4265, 2010 6. Rini BI, Escudier B, Tomczak P, et al: Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): A randomised phase 3 trial. Lancet 378:1931-1939, 2011 7. Escudier B, Eisen T, Stadler WM, et al: Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 356:125-134, 2007 8. Rini BI, Halabi S, Rosenberg JE, et al: Bevacizumab plus interferon alfa compared with interferon alfa monotherapy in patients with metastatic renal cell carcinoma: CALGB 90206. J Clin Oncol 26:54225428, 2008 9. Abraham RT, Gibbons JJ: The mammalian target of rapamycin signaling pathway: Twists and turns in the road to cancer therapy. Clin Cancer Res 13:3109-3114, 2007 10. Pantuck AJ, Seligson DB, Klatte T, et al: Prognostic relevance of the mTOR pathway in renal www.jco.org

with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: Jill Clancy, Pfizer (C); Kongming Wang, Pfizer (C); Andreas G. Niethammer, Pfizer (C); Subramanian Hariharan, Pfizer (C) Consultant or Advisory Role: Brian I. Rini, Pfizer (C); Joaquim Bellmunt, Pfizer (C); Bernard Escudier, Bayer HealthCare Pharmaceuticals (C), Pfizer (C), Novartis (C) Stock Ownership: Kongming Wang, Pfizer; Andreas G. Niethammer, Pfizer; Subramanian Hariharan, Pfizer Honoraria: Bernard Escudier, Bayer HealthCare Pharmaceuticals, Roche, Pfizer, Genentech, Novartis, AVEO Pharmaceuticals, GlaxoSmithKline Research Funding: Brian I. Rini, Pfizer Expert Testimony: None Patents: None Other Remuneration: None

AUTHOR CONTRIBUTIONS Conception and design: Brian I. Rini, Jill Clancy, Andreas G. Niethammer, Bernard Escudier Provision of study materials or patients: Brian I. Rini, Joaquim Bellmunt, Bernard Escudier Collection and assembly of data: Brian I. Rini, Joaquim Bellmunt, Andreas G. Niethammer, Bernard Escudier Data analysis and interpretation: All authors Manuscript writing: All authors Final approval of manuscript: All authors

cell carcinoma: Implications for molecular patient selection for targeted therapy. Cancer 109:22572267, 2007 11. Rini BI: Temsirolimus, an inhibitor of mammalian target of rapamycin. Clin Cancer Res 14:12861290, 2008 12. Atkins MB, Hidalgo M, Stadler WM, et al: Randomized phase II study of multiple dose levels of CCI779, a novel mammalian target of rapamycin kinase inhibitor, in patients with advanced refractory renal cell carcinoma. J Clin Oncol 22:909-918, 2004 13. Rini BI, Small EJ: Biology and clinical development of vascular endothelial growth factor-targeted therapy in renal cell carcinoma. J Clin Oncol 23: 1028-1043, 2005 14. Rini BI: Vascular endothelial growth factortargeted therapy in renal cell carcinoma: Current status and future directions. Clin Cancer Res 13: 1098-1106, 2007 15. Bukowski RM: Metastatic clear cell carcinoma of the kidney: Therapeutic role of bevacizumab. Cancer Manag Res 2:83-96, 2010 16. Yang JC, Haworth L, Sherry RM, et al: A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 349:427-434, 2003 17. Bukowski RM, Kabbinavar FF, Figlin RA, et al: Randomized phase II study of erlotinib combined with bevacizumab compared with bevacizumab alone in metastatic renal cell cancer. J Clin Oncol 25:4536-4541, 2007 18. Bellmunt J, Szczylik C, Feingold J, et al: Temsirolimus safety profile and management of toxic effects in patients with advanced renal cell carcinoma and poor prognostic features. Ann Oncol 19:1387-1392, 2008 19. Eisen T, Sternberg CN, Robert C, et al: Targeted therapies for renal cell carcinoma: Review of adverse event management strategies. J Natl Cancer Inst 104:93-113, 2012 20. Merchan JR, Liu G, Fitch T, et al: Phase I/II trial of CCI-779 and bevacizumab in stage IV renal

cell carcinoma: Phase I safety and activity results. J Clin Oncol 25:243s, 2007 (suppl 18s; abstr 5034) 21. Therasse P, Arbuck SG, Eisenhauer EA, et al: New guidelines to evaluate the response to treatment in solid tumors: European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205-216, 2000 22. Motzer RJ, Bacik J, Murphy BA, et al: Interferon-alfa as a comparative treatment for clinical trials of new therapies against advanced renal cell carcinoma. J Clin Oncol 20:289-296, 2002 23. Cella D, Yount S, Du H, et al: Development and validation of the Functional Assessment of Cancer Therapy-Kidney Symptom Index (FKSI). J Support Oncol 4:191-199, 2006 24. Cella D, Yount S, Brucker PS, et al: Development and validation of a scale to measure diseaserelated symptoms of kidney cancer. Value Health 10:285-293, 2007 25. Zhu X, Wu S, Dahut WL, et al: Risks of proteinuria and hypertension with bevacizumab, an antibody against vascular endothelial growth factor: Systematic review and meta-analysis. Am J Kidney Dis 49:186-193, 2007 26. Rodriguez-Pascual J, Cheng E, Maroto P, et al: Emergent toxicities associated with the use of mTOR inhibitors in patients with advanced renal carcinoma. Anticancer Drugs 21:478-486, 2010 27. Maroto JP, Hudes G, Dutcher JP, et al: Drugrelated pneumonitis in patients with advanced renal cell carcinoma treated with temsirolimus. J Clin Oncol 29:1750-1756, 2011 28. Merchan JR, Pitot HC, Qin R, et al: Final phase II safety and efficacy results of study MC0452: Phase I/II trial of CCI 779 and bevacizumab in advanced renal cell carcinoma. J Clin Oncol 29:300s, 2011 (suppl 15s; abstr 4548) 29. Ne´grier S, Gravis G, Pe´rol D, et al: Temsirolimus and bevacizumab, or sunitinib, or interferon alfa

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and bevacizumab for patients with advanced renal cell carcinoma (TORAVA): A randomised phase 2 trial. Lancet Oncol 12:673-680, 2011 30. McDermott DF, Manola J, Pins M, et al: The BEST trial (E2804): A randomized phase II study of VEGF, RAF kinase, and mTOR combination targeted therapy (CTT) with bevacizumab (bev), sorafenib (sor), and temsirolimus (tem) in advanced renal cell

carcinoma (RCC). J Clin Oncol 31, 2013 (suppl 6s; abstr 345) 31. Patel PH, Senico PL, Curiel RE, et al: Phase I study combining treatment with temsirolimus and sunitinib malate in patients with advanced renal cell carcinoma. Clin Genitourin Cancer 7:24-27, 2009 32. Feldman DR, Baum MS, Ginsberg MS, et al: Phase I trial of bevacizumab plus escalated doses of

sunitinib in patients with metastatic renal cell carcinoma. J Clin Oncol 27:1432-1439, 2009 33. Ravaud A, Barrios C, Anak O, et al: Randomized phase II study of first-line everolimus (EVE) ⫹ bevacizumab (BEV) versus interferon alpha-2a (IFN) ⫹ BEV in patients (Pts) with metastatic renal cell carcinoma (mRCC): RECORD-2. Ann Oncol 23: ix258, 2012 (suppl 9; abstr 7830)

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GLOSSARY TERMS

Bevacizumab: Also called Avastin, bevacizumab is a recombinant, humanized, monoclonal antibody that binds and neutralizes VEGF, thus acting as an antiangiogenic agent.

Temsirolimus: Also called CCI-779, temsirolimus is an inhibitor of mTOR, a member of the phophoinositide kinase-related family proteins.

IFN-␣ (interferon alfa): A cytokine with multiple postulated mechanisms that is used as antitumor therapy in several diseases, including metastatic renal cell carcinoma and hairy cell leukemia. mTOR: The mammalian target of rapamycin belongs to a pro-

tein complex (along with raptor and G␤L) that is used by cells to sense nutrients in the environment. mTOR is a serine/threonine kinase that is activated by Akt and regulates protein synthesis on the basis of nutrient availability. It was discovered when rapamycin, a drug used in transplantation, was shown to block cell growth presumably by blocking the action of mTOR.

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VEGF (vascular endothelial growth factor): VEGF is a cytokine that mediates numerous functions of endothelial cells including proliferation, migration, invasion, survival, and permeability. VEGF is also known as vascular permeability factor. VEGF naturally occurs as a glycoprotein and is critical for angiogenesis. Many tumors overexpress VEGF, which correlates to poor prognosis. VEGF-A, -B, -C, -D, and -E are members of the larger family of VEGF-related proteins.

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Temsirolimus/Bevacizumab v Interferon Alfa/Bevacizumab in mRCC

Acknowledgment We thank all the patients, investigators, and study centers that participated in this study. We also thank Christine H. Blood, PhD, and Teri O’Neill (Peloton Advantage, Parsippany, NJ) and Mariko Nagashima, PhD (Engage Scientific Solutions, Southport, CT), for medical writing support, funded by Pfizer. Appendix

In addition to the authors, the following investigators participated in the study: Argentina — Luis Enrique Fein, Juan Jose Zarba; Australia — Michael Paul Brown, Dusan Kotasek, Catherine Margaret Shannon; Belgium — Lionel D’Hondt, Jeroen Mebis, Sylvie Rottey, Dirk Schrijvers; Brazil — Gilberto de Castro Junior, Fabio Andre Franke, Andre Augusto Junior Gemeinder de Moraes, Daniel Herchenhorn, Sergio Vicente Serrano, Eliseu Jose Fleury Taveira, Jeferson Jose da Fonseca Vinholes, Manuela Zereu; Canada — Andre Blais; Chile — Hans Harbst, Mauricio Mahave, Eduardo Yanez; Colombia — Gustavo Adolfo Rojas Uribe; Czech Republic — Ivo Kocak, Bohuslav Melichar, Jan Schraml, Ivana Sirakova; France — Jean-Franc¸ois Berdah, Eric Legouffe, Didier Mayeur, Christian Pfister, Frederic Rolland, Christine Theodore, Jean-Marc Tourani; Germany — Juergen E. Gschwend, Roman Heuer, Hartmut Kirchner, Jan Roigas; Hong Kong — Wing Ming Ho, Wai Kay Philip Kwong, Wai-Tong Ng; Hungary — Marta Baki, Istvan Bodrogi, Lajos Hornyak, Laszlo Pajor, Tamas Pinter, Zsofia Polya; India — Chirag Desai, Vadavattath Padmanabhan Gangadharan, Mukul Goyal, Francis Vadakkumparambil James, Bhalchandra Kashyapi, Radheshyam Naik, Tarini Prasad Sahoo, Manju Sengar; Italy — Michele Battaglia, Pierfranco Conte, Lucio Crino, Stefano Iacobelli, Michele Milella, Fausto Roila; Korea, Republic of — Ho Yeong Lim, Sun Young Rha; Malaysia — Marniza Saad; Netherlands — Aart Beeker; Poland — Tomasz Demkow, Jacek Jassem, Piotr Koralewski, Elzbieta Staroslawska, Piotr Tomczak, Cezary Szczylik; Portugal — Jose Quintas; Russian Federation — Boris Y. Alekseev, Anna Valerievna Alyasova, Andrei Igorevich Gorelov, Oleg B. Karyakin, Rustem Shamilievich Khasanov, Petr V. Krivorotko, Alexander A. Mangushlo, Vsevolod Borisovich Matveev, Tatiana Petrovna Nikitina, Dmitry Nosov, Laslo Dulovich Roman; Serbia — Zoran Kovacevic, Sava Micic, Sinisa S. Radulovic; Singapore — Quan Sing Ng; Slovakia — Vladimir Balaz, Peter Bujdak, Peter Laurinc, Jozef Marencak; South Africa — Marius Bongers, Corlia Coetzee, Johann Petrus Jordaan, Keith Ian Maart, Paul Ruff; Spain — Miguel Angel Climent Duran, Ignacio Duran Martinez, Marta Lopez-Brea Piqueras, Jose Pablo Maroto Rey, Xavier Garcia del Muro Solans; Taiwan — John Wen Cheng Chang, Yen-Hwa Chang, Chia-Chi Lin, Su-Peng Yeh, Dah-Shyong Yu; Ukraine — Ipolit Kostinskyy, Roman Osypenkov, Olga Ponomareva, Roman Senyutovich; United Kingdom — Janet Elizabeth Brown, Simon Chowdhury, Simon J. Crabb, Robert Edward Hawkins; United States — Brad Patrick Baltz, Clyde Michael Jones, David Roderick Minor, Craig Randal Nichols, Nayyar Siddique, Jeffrey Alan Sosman, John Ainslie Thompson.

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Randomized phase III trial of temsirolimus and bevacizumab versus interferon alfa and bevacizumab in metastatic renal cell carcinoma: INTORACT trial.

To prospectively determine the efficacy of combination therapy with temsirolimus plus bevacizumab versus interferon alfa (IFN) plus bevacizumab in met...
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